JP2014237027A - Method for producing bioactive surface on endoprosthesis or on balloon of balloon catheter - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a bioactive surface on an endoprosthesis or on a balloon of a balloon catheter.SOLUTION: The surface (15) of an endoprosthesis or the surface (4) of a balloon (3) is softened, and moistened with a solution (6) of an active ingredient (7), and the solvent (8) is separated from the active ingredient (7). In addition, a balloon (3) of a balloon catheter (1) is disclosed, which comprises an uncoated surface (4), wherein an unencapsulated active ingredient (7) is embedded at least partially into the material of the surface (4). Furthermore, a balloon catheter (1) is described, which comprises a balloon (3) according to the present invention. In addition, an endoprosthesis, particularly a polymer stent is described, which comprises an uncoated surface (15), wherein an active ingredient (7) is embedded at least partially into the material of the surface (15).

Description

  The present invention relates to a method for producing a bioactive surface on an endoprosthesis or on the balloon of a balloon catheter. The invention further relates to balloon balloons and balloon catheters.

  So-called “minimally invasive methods” occupy an increasingly important position in medicine. In the field of radiology, reference is made to radiotherapy interventions. This makes an important contribution to the development of minimally invasive techniques and the necessary equipment and prosthetic devices made of suitable materials. Thus, today, small metal grids are placed in blood vessels as endovascular prostheses, so-called stents, by both cardiologists and radiologists in order to keep the blood vessels open. However, conventional stents often show vessel wall thickening due to cell proliferation or cell accumulation resulting in luminal stenosis in the area of the stent. In addition, balloon catheters are placed in blood vessels by cardiologists and by radiologists in order to dilate blood vessels. This operation also results in thickening of the blood vessel wall due to cell proliferation in the dilated region with luminal stenosis.

  This problem can be countered by releasing the drug from the endoprosthesis surface or the balloon surface of the balloon catheter, which can be equipped with a suitable polymer coating to improve drug loading and drug release. In general, an active substance dissolved in a solvent is applied to the surface of the endoprosthesis or the balloon catheter balloon, followed by evaporation of the solvent. The active substance then remains on the surface as a layer.

  Compared to this, Patent Document 1 and Patent Document 2 describe a method for realizing better adhesion of the active substance to the surface. Patent Document 1 describes a balloon catheter coated with a drug. In this case, in the first modification, the microcapsule filled with the active substance or the drug is surrounded by the folds on the balloon surface and mechanically held at the respective positions. In the second variant, the microcapsules are adhered to the balloon surface using a binder. In the scope of patent document 1, uncoated active substance crystals are also regarded as microcapsules.

  In Patent Document 2, a balloon catheter and a stent are described. Each of the surfaces is coated, and microcapsules filled with an active substance are completely embedded in the coating. In one embodiment, a balloon catheter is described in which microcapsules filled with an active substance on its uncoated surface are extruded during the manufacturing process. However, filling the microcapsules with the active substance and subsequently fixing or embedding the microcapsules on the balloon or stent surface is relatively laborious and as a result is an expensive method.

US Pat. No. 5,102,402 US Pat. No. 6,129,705

  Accordingly, it is a first object of the present invention to provide a method for advantageously producing a bioactive surface on an endoprosthesis or on the balloon of a balloon catheter. The second object of the present invention is to provide an advantageous balloon catheter balloon. A third problem is to provide an advantageous balloon catheter. A fourth problem is to provide an advantageous endoprosthesis.

The first subject is the method according to claim 1, the second subject is the balloon catheter balloon according to claim 19, the third subject is the balloon catheter according to claim 24, and the fourth subject. This problem is solved by the endoprosthesis according to claim 25. The dependent claims contain further advantageous embodiments of the invention. Features can be advantageous either alone or in combination with each other.

In the method according to the invention for the production of a bioactive surface on an endoprosthesis or on the balloon of a balloon catheter, the surface of the endoprosthesis or the surface of the balloon is softened and wetted with a solution of the active substance. Subsequently, the active substance solvent is separated.

D Here, this is a very simple and inexpensive method, in which all or part of the active substance is embedded or adhered to the surface as a result of softening the surface. In the scope of the method according to the invention, the principle of solvent welding is used. The method according to the present invention results in better adhesion to or within the surface than the method of merely depositing the active material on the surface. In addition, this is a much simpler and less expensive method compared to the methods described in US Pat.

  The surface of the endoprosthesis or the surface of the balloon is softened, in particular using a solvent, for example using a solution of the active substance. As the solvent, for example, dimethyl sulfoxide (DMSO), dioxane, dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane or chloroform may be used. These solvents are particularly miscible with water. Basically, the surface of the endoprosthesis or the surface of the balloon may be softened by other methods, for example by heat.

  When the surface of the endoprosthesis or the surface of the balloon is softened using a solution of the active substance, the first two procedural steps, namely the softening and wetting steps, can be performed simultaneously. The surface of the endoprosthesis or the surface of the balloon may be wetted with a solution of solvent or active substance, for example by dipping, spraying or pipetting.

  Advantageously, an endoprosthesis or balloon containing a polymer on its surface may be used. In particular, endoprostheses or balloons made of polymers may be used. For example, a balloon made of nylon or a nylon-Pebax mixture may be used.

  The active substance used is in particular tretinoin and / or a tretinoin derivative and / or an orphan receptor agonist and / or an elafin derivative and / or a corticosteroid and / or a steroid hormone and / or paclitaxel and / or taxol and / or Taxol derivatives and / or rapamune and / or tacrolimus and / or hydrophobic proteins and / or substances that alter cell proliferation may be included. As steroid hormones, for example, methylprednisolone, dexamethasone or estradiol is used.

  Advantageously, excess active substance and solvent can be removed from the wetted surface by movement of the endoprosthesis or balloon, such as centrifugal action or scraping. By movement of the endoprosthesis or balloon, in particular by spinning, it is achieved that the solvent, and thus the active substance, is evenly arranged on the surface of the endoprosthesis or balloon. This effectively prevents the formation of possible lumps.

  Furthermore, the endoprosthesis or balloon surface can be expanded before it softens. For example, the surface of an endoprosthesis or balloon can be magnified mechanically, thermally or chemically. The surface of the endoprosthesis or balloon can be enlarged, in particular by structuring or shaping. For example, the surface of an endoprosthesis or balloon can be structured or shaped by roughening. Advantageously, enlargement of the surface of the endoprosthesis or balloon creates a 5-50 μm deep and 5-50 μm wide recess on the surface.

  Furthermore, the surface of the endoprosthesis or the surface of the balloon may be used to wet with a solution of the active substance in a solvent that is miscible with water, with the active substance being soluble in distilled water at a maximum of 0.9 mg / ml. is there. In that case, the solvent can be separated from the active substance by immersing the wet endoprosthesis or the wet balloon in water. At that time, the water-insoluble active substance is precipitated, and a part is deposited on the surface of the endoprosthesis or balloon. Because the surface of the endoprosthesis or balloon is softened, all or part of the active substance is embedded in or at least deposited on the surface. As the water-soluble solvent, in particular, the above-mentioned solvents can be used.

  As an alternative to the previously described method of depositing the active substance on the surface by precipitation, the solvent can be separated from the active substance by volatilizing the solvent. In that case, a water-soluble solvent is not necessary.

  Basically, the surface of the endoprosthesis or balloon can be functionally coated with a polymer layer prior to producing the bioactive surface. In that case, the thickness of the functional polymer layer may be 10 to 1000 μm, preferably 200 to 400 μm. The surface of the endoprosthesis or balloon may be functionally coated using, for example, polyamino-p-xylylene-co-polyxylylene prior to producing the bioactive surface.

  In order to fabricate a functional polymer layer, the starting compounds (1), (2) and / or (3) of general structure produce gas phase monomers with increasing temperature and decreasing pressure, and lowering the temperature. And can be polymerized by the following formula:

R _{1, 2, 3, 4} : hydrogen atom, halogen atom, alkyl group or substituted alkyl group, aryl group or substituted aryl group, organic residue or radical, general structural group CO (OM -A), metallized group, hydroxyl group, amino group, carboxyl group, ester group, ether group, acid halide group, isocyanate group, sulfur-containing group, nitrogen-containing group, phosphorus-containing group, silicon A group containing
X, Y: hydrocarbon group m: number of repeating units = 1-20

Here, the temperature required to make the monomer is between 500 ° C. and 1000 ° C., and the required pressure is less than 500 Pa. The structure (1) or (2) in which the dimer is m = 1 can be decomposed into a monomer at a temperature of 600 ° C. to 900 ° C. and a pressure of less than 100 Pa, for example. Subsequent polymerization can be carried out at temperatures below 120 ° C.

  Basically, stents can be used as endoprostheses within the scope of the method according to the invention.

  The balloon of the balloon catheter according to the present invention includes an uncoated surface. The non-encapsulated active substance is at least partially embedded in the surface material. That is, all or part of the active substance is embedded in the surface. Even if only a part is embedded, the active substance adheres at least to the surface. The material of the surface of the balloon may in particular comprise a polymer, for example nylon or a nylon-pebax mixture. The balloon may be made of nylon or a nylon-pebax mixture.

  Active substances which are at least partially embedded in the surface are in particular tretinoin and / or tretinoin derivatives and / or orphan receptor agonists and / or elafin derivatives and / or corticosteroids and / or steroid hormones and / or paclitaxel and Taxol and / or taxol derivatives and / or rapamune and / or tacrolimus and / or hydrophobic proteins and / or substances that alter cell proliferation may be included. Steroid hormones may include, for example, methylprednisolone, dexamethasone, or estradiol.

The balloon catheter according to the present invention includes the balloon according to the present invention as described above. Both the balloon according to the invention and the balloon catheter according to the invention can be produced simply and at low cost, and in addition the reliable adhesion of the active substance to the surface is the same as a result of at least partial implantation. Has the advantage of being guaranteed.

An endoprosthesis according to the present invention includes an uncoated surface. The active substance is at least partially embedded in the surface material. The active substance may of course be completely embedded in the surface material. The endoprosthesis may in particular be a stent, preferably a polymer stent. Basically, the surface material may comprise a polymer.
Active substances which are at least partially embedded in the surface are in particular tretinoin and / or tretinoin derivatives and / or orphan receptor agonists and / or elafin derivatives and / or corticosteroids and / or steroid hormones and / or paclitaxel and Taxol and / or taxol derivatives and / or rapamune and / or tacrolimus and / or hydrophobic proteins and / or substances that alter cell proliferation may be included. Steroid hormones may include, for example, methylprednisolone, dexamethasone, or estradiol. The endoprosthesis according to the present invention has the same advantages as the balloon of the balloon catheter according to the present invention.

  Further features, properties, and advantages of the present invention are described below using examples and in conjunction with the accompanying figures. Features can be advantageous either alone or in combination with each other.

1 is a schematic view of a balloon catheter that is sprayed with a solution of an active substance. FIG. FIG. 6 is a schematic cross-sectional view of a portion of the balloon catheter surface of the balloon catheter where the active substance solution is present on the softened surface. It is a typical sectional view of a part of the surface of the balloon of the balloon catheter in which an active substance is embedded in the surface. It is a schematic diagram of a balloon catheter wetted with a solution of an active substance immersed in a water bath. FIG. 6 is a schematic cross-sectional view of a softened surface of a balloon of a balloon catheter, a portion of which is in water. 2 is a schematic cross-sectional view of a portion of the surface of a balloon of a balloon catheter in which an active substance is embedded in the roughened surface. FIG. FIG. 2 is a schematic cross-sectional view of a portion of a stent lattice frame whose surface has been softened and wetted with a solution of an active substance. FIG. 2 is a schematic cross-sectional view of a part of a lattice frame of a stent having an active substance embedded on its surface. FIG. 3 is a schematic cross-sectional view of a portion of a lattice frame of a stent functionally coated with a polymer and having a solution of an active agent on its softened polymer surface. 1 is a schematic cross-sectional view of a portion of a lattice frame of a stent functionally coated with a polymer and having an active agent embedded in the softened polymer surface. FIG.

  A first embodiment of the present invention is described in detail below using FIGS. FIG. 1 is a schematic view of a balloon catheter 1 to be sprayed using a spray device 5 containing a solution 6 of an active substance 7 in a solvent 8 that can be mixed with water. The balloon catheter 1 includes a catheter tube 2 and a balloon 3. The balloon 3 surrounds a part of the catheter tube 2. The balloon 3 is made of a polymer, such as nylon or a nylon-pebax mixture. The surface of the balloon 3 is sprayed using a spraying device 5 containing a solution 6 of the active substance 7 in a solvent 8 that is miscible with water and is thereby wetted. Instead of being sprayed, the balloon 3 of the balloon catheter 1 may be immersed or pipetted into a solvent that is miscible with water in the solution of the active substance. The solvent 8 softens the surface of the balloon 3.

  Basically, the surface of the balloon 3 may first be softened, for example using a softener, and subsequently wetted with a solution 6 of the active substance.

  FIG. 2 is a schematic cross-sectional view of a part of the surface of the balloon 3 of the balloon catheter 1 whose surface is wetted with a solution of the active substance 7. It is typical sectional drawing. The area of the surface 4 softened by the solvent 8 is indicated by reference numeral 12. On the softened surface 4 of the balloon 3 there is therefore a mixture of solvent 8 and active substance 7.

  The active substance 7 used is, for example, tretinoin and / or a tretinoin derivative and / or an orphan receptor agonist and / or an elafin derivative and / or a corticosteroid and / or a steroid hormone and / or paclitaxel and / or taxol and / or Taxol derivatives and / or rapamune and / or tacrolimus and / or hydrophobic proteins and / or substances that alter cell proliferation, and methylprednisolone, dexamethasone or estradiol may be used as steroid hormones. The solvent 8 may be, for example, dimethyl sulfoxide (DMSO), dioxane, dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane or chloroform.

  After wetting the surface 4, the solvent is vaporized or vaporized. Meanwhile, the active substance 7 is embedded in the surface 4 which is wholly or partly softened. This is schematically shown in FIG. FIG. 3 is a schematic cross-sectional view of a part of the surface 4 of the balloon 3 of the balloon catheter 1 in which the active substances 7 a and 7 b are embedded in the surface 4. The active substance partially embedded in the surface 4 is indicated by reference numeral 7a, and the active substance completely embedded in the surface 4 is indicated by reference numeral 7b.

  The second embodiment of the first embodiment is described in detail below using FIGS. 4 and 5. In this embodiment, the balloon 3 is first softened and wetted with a solution of the active substance 6, as described in connection with FIGS. Subsequently, unlike the previous embodiment, the solvent 8 does not evaporate and the active substance 7 is deposited on the softened surface 4 by precipitation.

  FIG. 4 is a schematic view of a balloon catheter wetted with a solution of active substance 6 immersed in a water bath. FIG. 4 shows a container 10 filled with water 9. The balloon 3 of the balloon catheter 1 is completely immersed in water 9. The softened and wetted surface 4 of the balloon 3 is then in direct contact with the water 9.

  FIG. 5 is a schematic cross-sectional view of the softened surface 4 of the balloon 3 of the balloon catheter 1, partly in water 9. As a result of direct contact between water 9 and water-miscible solvent 8, mixing of solvent 8 and water 9 proceeds gradually. This is schematically shown in FIG. On the contrary, the water-insoluble or at least sparingly water-soluble active substance 7 settles on the softened surface 3 of the balloon 3 and is embedded therein, as described in connection with FIG. In this way, the active substance 7 is separated from the solvent 8.

  After the active substance 7 has settled on the surface 4, the balloon 3 of the balloon catheter 1 is removed from the water bath. Optionally, water still remaining on the surface 4 of the balloon 3 may be subsequently vaporized. However, as a result of the embedding of the active substance 7 in the surface 4, the active substance 7 is in any case already tightly bound to the surface 4 of the balloon 3, so that the balloon 3 does not have to be essentially dried, i.e. wet. It may be.

  The third embodiment of the first example is described in detail below using FIG. In this embodiment, the surface 4 of the balloon 3 is first roughened before being softened. This is done in particular mechanically, chemically or thermally. In so doing, it is possible to make indentations on the surface 4 of the balloon 3, in particular 5-50 μm deep and 5-50 μm wide.

  Subsequently, the roughened surface 13 of the balloon 3 is softened and wetted with a solution 6 of the active substance, as described in the first two embodiments. For example, after the solvent 8 is vaporized or the active substance 7 is precipitated and separated, the active substance 7 is all or partly embedded in the roughened surface 13 of the balloon 3. This is schematically shown in FIG.

  FIG. 6 is a schematic cross-sectional view of a portion of the surface 13 of the balloon 3 of the balloon catheter 1 in which the active substance 7 is embedded in the roughened surface 13. The active substance partially embedded in the surface 13 is indicated by reference numeral 7a, and the active substance completely embedded in the surface is indicated by reference numeral 7b.

  In the following, the second embodiment will be described in detail using FIGS. Elements corresponding to the elements already described in the first embodiment are given the same reference numerals, and new details are described. This example relates to a stent to be coated with the active substance 7. The stent here is a polymer stent.

  FIG. 7 is a schematic cross-sectional view of a portion of a lattice frame 14 of a stent whose surface 15 has been softened and wetted with a solution of the active substance described in connection with FIG. The extent of the surface 15 of the softened lattice frame 14 is indicated by reference numeral 12. As solvent 8 or active substance 7, the substances mentioned in the first embodiment may be used. Subsequently, the solvent 8 is vaporized or the active substance 7 is precipitated and separated, in which case the active substance 7 is embedded in the surface 15 of the lattice frame 14. For details on this, reference is made to the embodiment of the first example.

  FIG. 8 is a schematic cross-sectional view of a part of a lattice frame 14 of a stent in which the active substance 7 is embedded in the surface 15. The active substance partially embedded in the surface 15 is indicated by reference numeral 7a, and the active substance completely embedded in the surface is indicated by reference numeral 7b.

  The second embodiment of the second embodiment is described in detail below using FIGS. 9 and 10. Unlike the previous embodiment, the stent 14, which in this case need not be a polymer stent, is first functionally coated with a polymer layer 16. To that end, for example, 700 ° C., 20 Pa dimer 4-amino- [2,2] -paracyclophane is decomposed into reactive monomers on the stent 14 and subsequently cooled onto the surface of the stent 14 cooled to about 20 ° C. Polymerize. The target thickness of the polymer coating is preferably 10 to 1000 μm, more preferably 200 to 400 μm.

  The polymer layer 16 produced in this way is thus a solution 6 of the active substance 7 in a solvent 8 that is directly miscible with water, as described with reference to FIG. 1 in the first embodiment. And may be wetted. Furthermore, the surface of the polymer coating 16 may first be enlarged, for example by roughening, before being softened and wetted. The method of enlarging the surface of the balloon 3 described in the first embodiment can be applied as possible enlargement on the surface of the polymer coating 16 of the present embodiment. The surface of the polymer coating 16 roughened in this way is subsequently wetted with a solution 6 of the active substance 7 in a solvent 8 which is miscible with water as described in the first embodiment. Softened.

  FIG. 9 is a schematic cross-sectional view of a portion of a lattice frame 14 of a stent, functionally coated with polymer 16 and having a solution of active substance 7 present on the softened polymer surface. The softened area of the polymer coating 16 is indicated by reference numeral 12. As solvent 8 or active substance 7, the substances mentioned in the first embodiment may be used.

  The solvent 8 on the softened and wetted surface of the polymer coating 16 is vaporized or as described in the example of the balloon 3 using FIGS. 4 and 5 in the first embodiment, Either the stent can be submerged in an aquarium, in which case the active substance 7 settles on and is embedded in the polymer-coated surface.

  When vaporizing, it is also possible to use a water-insoluble or poorly water-soluble solvent in all examples and embodiments.

The embedding of the active substance 7 into the polymer coating 16 achieved in the manner described is schematically shown in FIG.
FIG. 10 is a schematic cross-sectional view of a portion of a lattice frame 14 of a stent that is functionally coated with a polymer 16 and in which the active material 7 is embedded.
The active substance partially embedded in the polymer coating 16 is indicated by reference numeral 7a, and the active substance completely embedded in the surface is indicated by reference numeral 7b.

Claims (25)

  In a method for producing a bioactive surface on an endoprosthesis or on a balloon (3) of a balloon catheter (1), the endoprosthesis surface (15) or the balloon (3) surface (4) is softened and the surface of the endoprosthesis (15) or the method wherein the surface (4) of the balloon (3) is wetted with a solution (6) of the active substance (7) and the solvent (8) is separated from the active substance (7).   The method of claim 1, wherein the surface (15) of the endoprosthesis or the surface (4) of the balloon (3) is softened using the solvent (8).   Method according to claim 2, wherein the surface (15) of the endoprosthesis or the surface (4) of the balloon (3) is softened using the solvent (6) of the active substance (7).   The process according to any one of claims 1 to 3, wherein dimethyl sulfoxide (DMSO), dioxane, dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane or chloroform is used as the solvent (8).   5. The method according to any one of claims 1 to 4, wherein an endoprosthesis or balloon (3) is used, the surface (4, 15) comprising a polymer.   6. The method according to any one of claims 1 to 5, wherein an endoprosthesis or balloon (3) made of a polymer is used.   7. The method according to claim 6, wherein a balloon (3) made of nylon or nylon-pebax mixture is used.   The active substance used (7) is tretinoin and / or a tretinoin derivative and / or an orphan receptor agonist and / or an elafin derivative and / or a corticosteroid and / or a steroid hormone and / or paclitaxel and / or taxol and 8. The method according to any one of claims 1 to 7, comprising taxol derivatives and / or rapamune and / or tacrolimus and / or hydrophobic proteins and / or substances that alter cell proliferation.   The method according to claim 8, wherein methylprednisolone, dexamethasone or estradiol is used as the steroid hormone.   10. A method according to any one of the preceding claims, wherein the endoprosthesis or the surface (4, 15) of the balloon (3) is enlarged prior to softening.   11. Method according to claim 10, wherein the endoprosthesis or the surface (4, 15) of the balloon (3) is mechanically, thermally or chemically magnified.   12. Method according to claim 11, wherein the surface (4, 19) of the endoprosthesis or the balloon (3) is enlarged by structuring or shaping.   The method according to claim 12, wherein the surface (4, 19) of the endoprosthesis or the balloon (3) is structured or shaped by roughening.   From the enlargement of the surface (4, 15) of the endoprosthesis or the balloon (3), a recess with a depth of 5-50 μm and a width of 5-50 μm is created on the surface (4, 15). 14. The method according to any one of items 13.   The surface (15) of the endoprosthesis or the surface (4) of the balloon (3) is wetted by a solution (6) of the active substance (7) in a solvent (8) miscible with water, in which case The active substance (7) has a solubility in distilled water of up to 0.9 mg / ml and the wetted prosthesis or wetted balloon (3) is immersed in water (9), water-insoluble The active substance (7) is precipitated and partly deposited on the surface (4, 15), whereby the solvent (8) is separated from the active substance (7). 15. The method according to any one of 14.   15. The method according to any one of claims 1 to 14, wherein the solvent (8) is separated from the active substance (7) by vaporization of the solvent (8).   17. The endoprosthesis or the surface (4, 15) of the balloon (3) is functionally coated with a polymer layer (16) prior to producing a bioactive surface. The method described in 1.   The method according to any one of the preceding claims, wherein a stent (14) is used as an endoprosthesis.   In the balloon (3) of the balloon catheter (1) with an uncoated surface (4), the unencapsulated active substance (7) is at least partially embedded in the material of the surface (4). Characteristic balloon (3).   Balloon (3) according to claim 19, characterized in that the material of the surface (4) comprises a polymer.   21. Balloon (3) according to claim 20, characterized in that the polymer is nylon or a nylon-Pebax mixture.   The active substance used (7) is tretinoin and / or a tretinoin derivative and / or an orphan receptor agonist and / or an elafin derivative and / or a corticosteroid and / or a steroid hormone and / or paclitaxel and / or taxol and 22.// Taxol derivative and / or rapamune and / or tacrolimus and / or hydrophobic proteins and / or substances that alter cell proliferation, Balloon (3). 23. Balloon (3) according to claim 22, characterized in that the steroid hormone comprises methylprednisolone, dexamethasone or estradiol.   A balloon catheter (1), characterized in that it comprises a balloon (3) according to any one of claims 19 to 23.   An endoprosthesis comprising an uncoated surface (15), characterized in that the active substance (7) is at least partially embedded in the material of the surface (15).